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Mansouri, Larry
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Publications (10 of 62) Show all publications
Sasi, B. K., Martines, C., Xerxa, E., Porro, F., Kalkan, H., Fazio, R., . . . Efremov, D. G. (2019). Inhibition of SYK or BTK augments venetoclax sensitivity in SHP1-negative/BCL-2-positive diffuse large B-cell lymphoma. Leukemia, 33(10), 2416-2428
Open this publication in new window or tab >>Inhibition of SYK or BTK augments venetoclax sensitivity in SHP1-negative/BCL-2-positive diffuse large B-cell lymphoma
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2019 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 10, p. 2416-2428Article in journal (Refereed) Published
Abstract [en]

The BCL-2 inhibitor venetoclax has only limited activity in DLBCL despite frequent BCL-2 overexpression. Since constitutive activation of the B cell receptor (BCR) pathway has been reported in both ABC and GCB DLBCL, we investigated whether targeting SYK or BTK will increase sensitivity of DLBCL cells to venetoclax. We report that pharmacological inhibition of SYK or BTK synergistically enhances venetoclax sensitivity in BCL-2-positive DLBCL cell lines with an activated BCR pathway in vitro and in a xenograft model in vivo, despite the only modest direct cytotoxic effect. We further show that these sensitizing effects are associated with inhibition of the downstream PI3K/AKT pathway and changes in the expression of MCL-1, BIM, and HRK. In addition, we show that BCR-dependent GCB DLBCL cells are characterized by deficiency of the phosphatase SHP1, a key negative regulator of the BCR pathway. Re-expression of SHP1 in GCB DBLCL cells reduces SYK, BLNK, and GSK3 phosphorylation and induces corresponding changes in MCL1, BIM, and HRK expression. Together, these findings suggest that SHP1 deficiency is responsible for the constitutive activation of the BCR pathway in GCB DLBCL and identify SHP1 and BCL-2 as potential predictive markers for response to treatment with a venetoclax/BCR inhibitor combination.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-395723 (URN)10.1038/s41375-019-0442-8 (DOI)000488517000007 ()30872780 (PubMedID)
Funder
EU, Horizon 2020, 692180-STREAMH2020-TWINN-2015Swedish Cancer SocietySwedish Research Council
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
Papakonstantinou, N., Ntoufa, S., Tsagiopoulou, M., Moysiadis, T., Bhoi, S., Malousi, A., . . . Stamatopoulos, K. (2019). Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia. International Journal of Cancer, 144(11), 2695-2706
Open this publication in new window or tab >>Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 11, p. 2695-2706Article in journal (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U-CLL). Subset #6 (IGHV1-69/IGKV3-20) is less aggressive compared to subset #8 (IGHV4-39/IGKV1(D)-39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome-wide DNA methylation profiles in subsets #6 and #8 as well as other U-CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U-CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional nonsubset U-CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro-survival effect was also supported by siRNA-mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness. What's new? In chronic lymphocytic leukemia (CLL), cases with unmutated immunoglobulin receptors (U-CLL) are generally associated with inferior outcome, albeit still displaying considerable heterogeneity. Might such differences in CLL progression be explained by epigenetics? In this study, the authors found that an unusually aggressive subset of CLLs called subset #8 has a distinctive DNA-methylation profile. They also found that p63 is a novel pro-survival factor for CLL cells. These molecular studies may lead to new prognostic biomarkers, and possibly new therapeutic targets, for CLL.

Keywords
CLL, stereotypy, DNA methylation, gene expression, TP63
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-384059 (URN)10.1002/ijc.31999 (DOI)000467099500009 ()30447004 (PubMedID)
Funder
EU, Horizon 2020, 644906Swedish Cancer SocietyKnut and Alice Wallenberg FoundationEU, Horizon 2020, 692298Swedish Research CouncilEU, Horizon 2020, 702714
Note

De 3 första författarna delar förstaförfattarskapet.

Available from: 2019-06-20 Created: 2019-06-20 Last updated: 2019-06-20Bibliographically approved
Baliakas, P., Moysiadis, T., Hadzidimitriou, A., Xochelli, A., Jeromin, S., Agathangelidis, A., . . . Stamatopoulos, K. (2019). Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia. Haematologica, 104(2), 360-369
Open this publication in new window or tab >>Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia
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2019 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 2, p. 360-369Article in journal (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia (CLL) patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinico-biological differences. Considering this, we assessed prognosis separately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet A M-CLL patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to first -treatment and a treatment probability at Five and ten years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet A U-CLL patients, besides TP53 abnormalities, del(11q) and/or ST3B1 mutations were associated with the shortest time-to-First treatment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage CLL patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in CLL.

Place, publisher, year, edition, pages
FERRATA STORTI FOUNDATION, 2019
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-377215 (URN)10.3324/haematol.2018.195032 (DOI)000457460800032 ()30262567 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Wasik, A. M., Wu, C., Mansouri, L., Rosenquist, R., Pan-Hammarstrom, Q. & Sander, B. (2018). Clinical and functional impact of recurrent S1PR1 mutations in mantle cell lymphoma. BLOOD ADVANCES, 2(6), 621-625
Open this publication in new window or tab >>Clinical and functional impact of recurrent S1PR1 mutations in mantle cell lymphoma
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2018 (English)In: BLOOD ADVANCES, ISSN 2473-9529, Vol. 2, no 6, p. 621-625Article in journal (Refereed) Published
Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY, 2018
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-354348 (URN)10.1182/bloodadvances.2017014860 (DOI)000428386900004 ()29549086 (PubMedID)
Funder
Swedish Research CouncilEU, European Research Council, RNAEDIT-649019Knut and Alice Wallenberg Foundation
Available from: 2018-06-27 Created: 2018-06-27 Last updated: 2018-06-27Bibliographically approved
Mansouri, L., Wierzbinska, J. A., Plass, C. & Rosenquist, R. (2018). Epigenetic deregulation in chronic lymphocytic leukemia: Clinical and biological impact. Seminars in Cancer Biology, 51, 1-11
Open this publication in new window or tab >>Epigenetic deregulation in chronic lymphocytic leukemia: Clinical and biological impact
2018 (English)In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 51, p. 1-11Article in journal (Refereed) Published
Abstract [en]

Deregulated transcriptional control caused by aberrant DNA methylation and/or histone modifications is a hallmark of cancer cells. In chronic lymphocytic leukemia (CLL), the most common adult leukemia, the epigenetic 'landscape' has added a new layer of complexity to our understanding of this clinically and biologically heterogeneous disease. Early studies identified aberrant DNA methylation, often based on single gene promoter analysis with both biological and clinical impact. Subsequent genome-wide profiling studies revealed differential DNA methylation between CLLs and controls and in prognostics subgroups of the disease. From these studies, it became apparent that DNA methylation in regions outside of promoters, such as enhancers, is important for the regulation of coding genes as well as for the regulation of non-coding RNAs. Although DNA methylation profiles are reportedly stable over time and in relation to therapy, a higher epigenetic heterogeneity or 'burden' is seen in more aggressive CLL subgroups, albeit as non-recurrent 'passenger' events. More recently, DNA methylation profiles in CLL analyzed in relation to differentiating normal B-cell populations revealed that the majority of the CLL epigenome reflects the epigenomes present in the cell of origin and that only a small fraction of the epigenetic alterations represents truly CLL-specific changes. Furthermore, CLL patients can be grouped into at least three clinically relevant epigenetic subgroups, potentially originating from different cells at various stages of differentiation and associated with distinct outcomes. In this review, we summarize the current understanding of the DNA methylome in CLL, the role of histone modifying enzymes, highlight insights derived from animal models and attempts made to target epigenetic regulators in CLL along with the future directions of this rapidly advancing field.

Place, publisher, year, edition, pages
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2018
Keywords
Chronic lymphocytic leukemia, DNA methylation, Histone modification, Outcome, Prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-364003 (URN)10.1016/j.semcancer.2018.02.001 (DOI)000442066000002 ()29427646 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Cancer SocietyThe Karolinska Institutet's Research Foundation
Available from: 2018-11-05 Created: 2018-11-05 Last updated: 2018-11-05Bibliographically approved
Went, M., Sud, A., Speedy, H., Sunter, N. J., Foersti, A., Law, P. J., . . . Houlston, R. S. (2018). Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology. Blood Cancer Journal, 9, Article ID 1.
Open this publication in new window or tab >>Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology
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2018 (English)In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 9, article id 1Article in journal (Refereed) Published
Abstract [en]

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R-g = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChlP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.

National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-374121 (URN)10.1038/s41408-018-0162-8 (DOI)000454815100001 ()30602759 (PubMedID)
Funder
Swedish Foundation for Strategic Research , KF10-0009Knut and Alice Wallenberg Foundation, 2012.0193Swedish Research Council, 2012-1753EU, FP7, Seventh Framework Programme, LSHC-Ct-2006-037602Marianne and Marcus Wallenberg Foundation
Available from: 2019-01-23 Created: 2019-01-23 Last updated: 2019-01-23Bibliographically approved
Baliakas, P., Mattsson, M., Hadzidimitriou, A., Minga, E., Agathangelidis, A., Sutton, L. A., . . . Stamatopoulos, K. (2018). No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy [Letter to the editor]. Haematologica, 103(4), E158-E161
Open this publication in new window or tab >>No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy
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2018 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 4, p. E158-E161Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
FERRATA STORTI FOUNDATION, 2018
National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-356894 (URN)10.3324/haematol.2017.182634 (DOI)000428242100006 ()29269523 (PubMedID)
Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-09Bibliographically approved
Sasi, B. K., Turkalj, S., Kalkan, H., Porro, F., Bojnik, E., Pyrzynska, B., . . . Efremov, D. G. (2018). SHP1 Deficiency Is Responsible for the Constitutive Activation of the BCR Pathway in GCB DLBCL. Paper presented at 60th Annual Meeting of the American-Society-of-Hematology (ASH), DEC 01-04, 2018, San Diego, CA. Blood, 132
Open this publication in new window or tab >>SHP1 Deficiency Is Responsible for the Constitutive Activation of the BCR Pathway in GCB DLBCL
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2018 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY, 2018
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-378245 (URN)10.1182/blood-2018-99-118120 (DOI)000454842800061 ()
Conference
60th Annual Meeting of the American-Society-of-Hematology (ASH), DEC 01-04, 2018, San Diego, CA
Available from: 2019-03-08 Created: 2019-03-08 Last updated: 2019-03-08Bibliographically approved
Xochelli, A., Baliakas, P., Kavakiotis, I., Agathangelidis, A., Sutton, L. A., Minga, E., . . . Stamatopoulos, K. (2017). Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes. Clinical Cancer Research, 23(17), 5292-5301
Open this publication in new window or tab >>Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes
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2017 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 17, p. 5292-5301Article in journal (Refereed) Published
Abstract [en]

Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.  

Keywords
B-cell receptors, gene mutational status, antigen receptors, CD38 expression, genomic aberrations, sequence-analysis, I-antigen, immunoglobulin, antibodies, dna
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-334402 (URN)10.1158/1078-0432.CCR-16-3100 (DOI)000409037300034 ()28536306 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2017-12-08 Created: 2017-12-08 Last updated: 2017-12-11Bibliographically approved
Bhoi, S., Mansouri, L., Castellano, G., Sutton, L. A., Papakonstantinou, N., Queiros, A., . . . Rosenquist, R. (2017). DNA METHYLATION PROFILING IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS CARRYING STEREOTYPED B-CELL RECEPTORS: A DIFFERENT CELLULAR ORIGIN FOR SUBSET #2?. Paper presented at 22nd Congress of the European-Hematology-Association, JUN 22-25, 2017, Madrid, SPAIN. Haematologica, 102(Suppl. 2), 68-68, Article ID P244.
Open this publication in new window or tab >>DNA METHYLATION PROFILING IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS CARRYING STEREOTYPED B-CELL RECEPTORS: A DIFFERENT CELLULAR ORIGIN FOR SUBSET #2?
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2017 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no Suppl. 2, p. 68-68, article id P244Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
FERRATA STORTI FOUNDATION, 2017
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-377412 (URN)000404127001140 ()
Conference
22nd Congress of the European-Hematology-Association, JUN 22-25, 2017, Madrid, SPAIN
Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-02-20Bibliographically approved
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